The proposed study is concerned with an evaluation of the antiarrhythmic activity of a series of compounds synthesized in our Medicinal Chemistry Laboratories. Many of the drugs to be studied are related structurally to the beta-adrenergic receptor blocking agents. In addition, the quaternary analog of each compound has been synthesized and will be examined for its pharmacological properties. The drugs will be studied for potential antiarrhythmic activity against digitalis-induced arrhythmias as well as rhythm disorders associated with acute myocardial infarction. All agents will be examined for their ability to protect the heart against the development of ventricular fibrillation by studying the agents in animals subjected to periods of myocardial ischemia followed by sudden restoration of coronary blood flow and by studying the influence of the drugs upon the electrical ventricular fibrillation threshold. The detailed cardiovascular pharmacology of these agents will be explored. Interest will be centered on their spectrum of antiarrhythmic activity as well as their hemodynamic effects and their electrophysiologic actions. An attempt will be made to better understand the relationships between chemical structure and antiarrhythmic activity. Recent studies in this laboratory indicate that such a relationship does exist and that conversion of an active antiarrhythmic drug to its quaternary ammonium derivative increases its antiarrhythmic spectrum and reduces its unwanted effects upon the cardiovascular and central nervous systems. Tissue distribution, myocardial tissue in particular, will be studied with respect to antiarrhythmic activity through the use of a series of compounds in which an iodine I125 atom is a stable part of the molecule. The hope is to gain a better understanding of the relationship between drug blood levels and myocardial tissue levels and antiarrhythmic activity. The main objective is to obtain a drug(s) that is effective as an antiarrhythmic agent, especially when tested against arrhythmias due to myocardial ischemia, but has minimal hemodynamic effects and undesirable electrophysiologic actions. BIBLIOGRAPHIC REFERENCES: Kniffen, F. J., Lomas, T. E., Counsell, R. E. and Lucchesi, B. R.: The antiarrhythmic actions of bretylium and its O-iodo-benzyl trimethylammonium analog, UM-360. J. Pharmacol. Exp. Therap (Text Truncated - Exceeds Capacity)